DETAILED CORRESPONDENCE
Status of the Application
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on April 16, 2026 has been entered.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-3, 6, 7, 22, and 23 are pending in the application.
Applicant’s amendment to the claims, filed April 16, 2026, is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Applicant’s remarks filed April 16, 2026 in response to the final rejection mailed December 17, 2025 have been fully considered.
Claim 21 has been canceled by the claim amendment filed April 16, 2026 and all rejections previously applied to claim 21 are withdrawn.
The text of those sections of Title 35 U.S. Code not included in the instant action can be found in a prior Office action.
Restriction/Election
In response to a requirement for restriction/election filed March 27, 2024, applicant elected without traverse the invention of Group I, pending claims 1-3, 6, 7, 22, and 23, the species of phenylalanine ammonia lyase (claim 2), the species of Y0001 (no longer recited in the claims), and the species of N-caffeoyltyramine (claims 6 and 7) in the reply filed on May 28, 2024.
All pending claims are drawn to the elected invention of Group I. Claims 1-3, 6, 7, 22, and 23 are being examined on the merits with claims 2, 6, and 7 being examined to the extent the claims read on the elected subject matter.
Claim Objections
Claim 1 is objected to for reciting the conjunction “and” between parts (e) and (f) and in the interest of improving claim form, it is suggested that the conjunction “and” between parts (e) and (f) be deleted and added between parts (f) and (g).
RESPONSE TO REMARKS: Applicant argues claim 1 has been amended to remove the conjunction after part (e) and insert it after part (f), however, no such amendment has been made to claim 1.
Claim Rejections - 35 USC § 112(b)
The rejection of claims 1-3, 6, 7, 22, and 23 under 35 U.S.C. 112(b) as being indefinite in the recitation of “said cinnamate-4-hydroxylase is functionally expressed with a compatible cytochrome P450 reductase” in claim 1 part (f) is withdrawn in view of applicant’s amendment to claim 1 to delete the phrase at issue.
Claims 1-3, 6, 7, 22 and 23 are newly rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention. This rejection is necessitated by the instant amendment to claim 1.
Claim 1 (claims 2, 3, 6, 7, 22 and 23 dependent therefrom) is confusing in the recitation of “(g) a nucleic acid molecule encoding a coumaroyl CoA ligase capable of ligating CoA to one or more of cinnamate, p-coumaric acid, caffeic acid, ferulic acid, and sinapic acid into the corresponding CoA thiol esters that selectively ligates CoA to one or more of cinnamate, p-coumaric acid, caffeic acid, ferulic acid, or sinapic acid” (italics added for emphasis). In the interest of advancing prosecution, applicant may consider an amendment to delete the phrase “that selectively ligates CoA to one or more of cinnamate, p-coumaric acid, caffeic acid, ferulic acid, or sinapic acid.”
Claim Rejections - 35 USC § 112(a)
Claims 1-3, 6, 7, 22 and 23 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
MPEP § 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims”. See also MPEP 714.02. MPEP § 2163.II.A.3.(b) further states, “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112, para. 1, as lacking adequate written description”. According to MPEP § 2163.I.B, “While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure” and “The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117.”
Claim 1 (claims 2, 3, 6, 7, 22, and 23 dependent therefrom) was amended on October 8, 2025 to recite (in relevant part) “(g) a nucleic acid molecule encoding a coumaroyl CoA ligase that selectively ligates CoA to one or more of cinnamate, p-coumaric acid, caffeic acid, ferulic acid, or sinapic acid,” and as amended on April 16, 2026, claim 1 (claims 2, 3, 6, 7, 22, and 23 dependent therefrom) recites (in relevant part) “(g) a nucleic acid molecule encoding a coumaroyl CoA ligase…that selectively ligates CoA to one or more of cinnamate, p-coumaric acid, caffeic acid, ferulic acid, or sinapic acid.”
According to the remarks filed October 8, 2025 at p. 6, “[s]upport for the claim amendments can be found in the specification as filed, for example at paragraphs [0041], [0046], [0047], [0057], and [0107],” and according to the remarks filed April 16, 2026 at p. 6, “[s]upport for the claim amendments can be found in the specification and claims as originally filed, for example at paragraphs n paragraphs [0006], [0009], [0011], [0046]-[0047], and Figures 1-2.” However, there is no apparent descriptive support in the original application for the limitation “a nucleic acid molecule encoding a coumaroyl CoA ligase…that selectively ligates CoA to one or more of cinnamate, p-coumaric acid, caffeic acid, ferulic acid, or sinapic acid.” Applicant is invited to show support for the limitation at issue.
RESPONSE TO REMARKS: Applicant argues the rejection is obviated by amendment to recite the exact language of the as-filed specification for part (g), however, this is not found persuasive because the unsupported limitation is still present in part (g) of claim 1.
Claim Rejections - 35 USC § 103
The rejection of claim 3 under 35 U.S.C. 103 as being unpatentable over Hagel, J. (“Metabolic Engineering of Hydroxycinnamic Acid Amide in Nicotiana tabacum”, Dissertation, University of Calgary, 2004; cited on Form PTO-892 mailed on June 12, 2024; hereafter “Hagel”) in view of
Kang et al. (Biotechnol. Lett. 31:1469-1475, 2009; cited on the IDS filed on November 2, 2022; hereafter “Kang”),
Jiang, H. (“Metabolic Engineering of the Phenylpropanoid Pathway in Saccharomyces cerevisiae”, Dissertation, Purdue University, 2005; cited on Form PTO-892 mailed on June 12, 2024; hereafter “Jiang”),
Trantas et al. (Metabolic Engineer. 11:355-366, 2009; cited on Form PTO-892 filed December 17, 2025; hereafter “Trantas”) and
Koopman et al. (Microbial Cell Factories 11:155, 2012, 15 pages; cited on the IDS filed on November 2, 2022; hereafter “Koopman”), and
as evidenced by IUBMB Enzyme Nomenclature for EC 6.2.1.12 (obtained from https://iubmb.qmul.ac.uk/enzyme/EC6/2/1/12.html on January 30, 2025, 1 page; cited on Form PTO-892 mailed on February 4, 2025; hereafter “IUBMB”)
as applied to claims 1, 2, 6, 7, 22, and 23, and further in view of Katz et al. (US 2015/0361455 A1; cited on the IDS filed November 2, 2022)
is withdrawn in view of applicant’s amendment to claim 3 to replace “methionine” with “S-adenosylmethionine.”
Claims 1, 2, 6, 7, 22, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Hagel in view of Kang, Jiang, Trantas, and Koopman, and as evidenced by IUBMB.
As amended, the claims are drawn to a recombinant eukaryotic host cell capable of producing a tyramine containing hydroxycinnamic acid amide, the recombinant eukaryotic host cell comprising:
one or more nucleic acid molecules encoding one or more enzymes capable of overproduction of L-tyrosine or L-phenylalanine, wherein at least one of said enzymes is a feedback-resistant 3-deoxy-D-arabino-heptulosonate-7-phosphate synthase;
one or more nucleic acid molecules encoding one or more enzymes of a phenylpropanoid CoA pathway for making a hydroxycinnamoyl-CoA ester;
a nucleic acid molecule encoding a tyrosine decarboxylase that decarboxylates tyrosine to produce tyramine;
a nucleic acid molecule encoding a tyramine N-hydroxycinnamoyltransferase;
a nucleic acid molecule encoding a phenylalanine ammonia lyase to convert L-phenylalanine to cinnamic acid;
a nucleic acid molecule encoding a cinnamate-4-hydroxylase to convert cinnamic acid to coumaric acid a nucleic acid molecule encoding a cytochrome P450 reductase, wherein said cinnamate-4-hydroxylase and the cytochrome P450 reductase are coexpressed;
a nucleic acid molecule encoding a coumaroyl CoA ligase capable of ligating CoA to one or more of cinnamate, p-coumaric acid, caffeic acid, ferulic acid, and sinapic acid into the corresponding CoA thiol esters that selectively ligates CoA to one or more of cinnamate, p-coumaric acid, caffeic acid, ferulic acid, or sinapic acid;
wherein the recombinant eukaryotic host cell is a recombinant yeast strain, and
wherein the recombinant eukaryotic host cell comprises a knockout of ARO10 and a knockout of PDC5.
The following explanation is provided for clarity of the record. The rejection refers to the enzyme abbreviations DAHP synthase, PAL, C4H, CPR, 4CL, TYDC, and THT.
DAHP is the abbreviation for 3-deoxy-D-arabino-heptulosonate-7-phosphate and DAHP synthase corresponds to “one or more enzymes capable of overproduction of L-tyrosine” in part (a) of claim 1.
TYDC is the abbreviation for tyrosine decarboxylase and corresponds to a tyrosine decarboxylase that decarboxylates tyrosine to produce tyramine in part (c) of claim 1.
THT is the abbreviation for tyramine N-hydroxycinnamoyltransferase and corresponds to part (d) of claim 1.
PAL is the abbreviation for phenylalanine ammonia lyase and corresponds to “one or more enzymes of a phenylpropanoid CoA pathway for making a hydroxycinnamoyl-CoA ester” in part (b) of claim 1, “a phenylalanine ammonia lyase to convert L-phenylalanine to cinnamic acid” in part (e) of claim 1, and “phenylalanine ammonia lyase” in claim 2.
C4H is the abbreviation for cinnamate-4-hydrolyase and corresponds to “one or more enzymes of a phenylpropanoid CoA pathway for making a hydroxycinnamoyl-CoA ester” in part (b) of claim 1 and “a cinnamate-4-hydroxylase to convert cinnamic acid to coumaric acid” in part (f) of claim 1.
CPR is the abbreviation for cytochrome P450 reductase and corresponds to “one or more enzymes of a phenylpropanoid CoA pathway for making a hydroxycinnamoyl-CoA ester” in part (b) of claim 1 and “cytochrome P450 reductase” in part (f) of claim 1.
4CL is the abbreviation for 4-coumarate:CoA ligase or as evidenced by IUBMB, is alternatively referred to as p-coumaroyl CoA ligase (see “Accepted name” and “Other name(s)”). 4CL corresponds to “one or more enzymes of a phenylpropanoid CoA pathway for making a hydroxycinnamoyl-CoA ester” in part (b) of claim 1 and “a coumaroyl CoA ligase capable of ligating CoA to one or more of cinnamate, p-coumaric acid, caffeic acid, ferulic acid, and sinapic acid into the corresponding CoA thiol esters” in part (g) of claim 1.
Figure 3 of Hagel (reproduced in Appendix A for convenience and clarity of the record) shows a simplified scheme for the biosynthesis of the hydroxycinnamic acid amides, 4-coumaroyltyramine and feruloyltyramine, in plants (pp. 10-11). Hagel teaches important enzymes in the biosynthesis of hydroxycinnamic acid amides in plants including PAL, 4CL, TYDC, and THT (p. 14, bottom to p. 24, middle). Hagel teaches 4CL catalyzes the last step of the general phenylpropanoid pathway and converts 4-coumaric acid to the corresponding CoA ester (p. 15, first full paragraph). Figure 7 of Hagel (reproduced in Appendix A for convenience and clarity of the record) depicts the phenylpropanoid pathway showing biosynthesis of hydroxycinnamic acid amides, which includes C4H to convert cinnamate to 4-coumarate (pp. 31-32). Hagel teaches a transgenic tobacco plant designated as “TYDC x THT,” which is engineered to overexpress TYDC and THT for the increased production of tyramine-derived hydroxycinnamic acid amide (p. iii, Abstract; p. 49, second paragraph).
Hagel teaches engineering a tobacco plant for production of tyramine-derived hydroxycinnamic acid amide but does not teach a recombinant yeast strain for production of hydroxycinnamic acid amides.
Kang teaches tyramine derivatives are synthesized in trace amounts in plants and that in contrast to using plants as hosts for producing plant specific secondary metabolites, the use of microbes provides a good alternative for the mass production of scarce bioactive compounds (p. 1469, column 1, bottom to p. 1470, column 2, top). Kang teaches an E. coli modified to express 4CL and THT, which, when combined with tyramine, produced large amounts of feruloyltyramine, 4-coumaroyltyramine, and caffeoyltyramine (p. 1470, sentence bridging columns 1-2).
Jiang teaches that S. cerevisiae has some advantages over E. coli for expressing eukaryotic heterologous proteins (p. 14, bottom) and Trantas teaches S. cerevisiae as a eukaryotic organism has transcriptional and translational mechanisms similar in basic respects to those of plants, making yeast a suitable single-celled organism for the production of secondary metabolites through the heterologous expression of plant genes (p. 361, column 2, bottom). Jiang teaches the phenylpropanoid pathway in plants (p. 10, Figure 1.2, reproduced in Appendix B for convenience and clarity of the record) including PAL, C4H, and 4CL (p. 16, middle) and suggests transferring a plant phenylpropanoid pathway into yeast for the production of desired downstream products (p. 16, middle). Similar to Jiang, Trantas discusses the phenylpropanoid pathway in plants including PAL, C4H, and 4CL (p. 356, column 1, middle), however, Trantas teaches the additional expression of CPR with the phenylpropanoid pathway enzymes enhanced p-coumaric acid production by 4-fold and teaches the phenylpropanoid pathway in yeast requires the support of a plant CPR (p. 359, column 2). Trantas teaches a metabolically engineered S. cerevisiae strain expressing PAL, C4H, 4CL, and CPR for production of downstream products from the intermediate 4-coumaroyl-CoA (p. 360, Figure 2, reproduced in Appendix C for convenience and clarity of the record).
In view of the combined teachings of Hagel, Kang, Jiang, and Trantas, it would have been obvious to one of ordinary skill in the art before the effective filing date for a S. cerevisiae expressing PAL, C4H, 4CL, CPR, TYDC, and THT in order to produce hydroxycinnamic acid amides.
One would have been motivated to do so because while Hagel teaches recombinantly expressing TYDC and THT in a plant in order to convert 4-coumaroyl-CoA of the phenylpropanoid pathway and tyramine to hydroxycinnamic acid amides, Kang teaches that tyramine derivatives are synthesized in only trace amounts in plants. As an alternative, Kang teaches using microbes for the mass production of scarce bioactive compounds, and while Kang selected E. coli as the microbe for production of hydroxycinnamic acid amides, Jiang acknowledges that S. cerevisiae has advantages over E. coli for expression of eukaryotic genes and Trantas teaches S. cerevisiae as a eukaryotic organism has transcriptional and translational mechanisms similar in basic respects to those of plants making yeast a suitable single-celled organism for the production of secondary metabolites through the heterologous expression of plant genes. Trantas teaches a metabolically engineering S. cerevisiae with the plant phenylpropanoid pathway enzymes PAL, C4H, 4CL, and CPR to produce the 4-coumaroyl-CoA intermediate as a metabolite for biosynthesis of plant-based compounds.
One would have expected success because the TYDC and THT taught by Hagel and Kang are eukaryotic enzymes and Jiang taught S. cerevisiae as a suitable host for the expression of eukaryotic polypeptides and Trantas taught S. cerevisiae as a eukaryotic organism has transcriptional and translational mechanisms similar in basic respects to those of plants making yeast a suitable single-celled organism for the production of secondary metabolites through the heterologous expression of plant genes.
Regarding the limitations “(a) one or more nucleic acid molecules encoding one or more enzymes capable of overproduction of L-tyrosine or L-phenylalanine, wherein at least one of said enzymes is a feedback-resistant 3-deoxy-D-arabino-heptulosonate-7-phosphate synthase” and “wherein the recombinant eukaryotic host cell comprises a knockout of ARO10 and a knockout of PDC5” in claim 1, as shown by Hagel, tyrosine and phenylalanine are substrates for hydroxycinnamic acid amide production (p. 10 and Figure 3) and Jiang teaches that L-Tyr pool size is limiting in S. cerevisiae overexpressing PAL (p. 59) and the S. cerevisiae could be engineered to increase flux to L-Phe and L-Tyr (p. 98, bottom). Jiang teaches a DAHP synthase mutant free from feedback inhibition and expressing the mutant DAHP synthase increased L-Tyr production (p. 99). Koopman teaches expressing a mutant DAHP synthase in S. cerevisiae and knocking out ARO10 and PDC5 to enhance the availability of the aromatic amino acids L-Phe and L-Tyr (p. 5, columns 1-2).
In view of the teachings of Jiang and Koopman, it would have been obvious to one of ordinary skill in the art before the effective filing date to further modify a S. cerevisiae expressing PAL, C4H, 4CL, CPR, TYDC, and THT as taught and/or suggested by the combination of Hagel, Kang, Jiang, and Trantas to express a feedback-resistant DAHP synthase and to knockout ARO10 and PDC5.
One would have been motivated and would have expected success because Hagel taught tyrosine and phenylalanine are substrates for hydroxycinnamic acid amide production, Jiang taught the S. cerevisiae could be engineered to increase flux to L-Phe and L-Tyr, which are aromatic amino acids, Jiang and Koopman taught expressing a feedback-resistant DAHP synthase to increase aromatic amino acid production, and Koopman taught knocking out ARO10 and PDC5 to reduce the diversion of aromatic amino acid biosynthesis.
Therefore, claims 1, 2, 6, 7, 22, and 23 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claim 3 is newly rejected under 35 U.S.C. 103 as being unpatentable over Hagel in view of Kang, Jiang, Trantas, and Koopman and as evidenced by IUBMB as applied to claims 1, 2, 6, 7, 22, and 23 above, and further in view of Cao et al. (Ann. Microbiol. 62:1395-1402, 2012; cited on the attached Form PTO-892; hereafter “Cao”).
As amended, claim 3 is drawn to the recombinant eukaryotic host cell of claim 1, wherein said host cell further overproduces S-aenosylmethionine.
The relevant teachings of Hagel, Kang, Jiang, Trantas, and Koopman and evidentiary reference IUBMB as applied to claims 1, 2, 6, 7, 22, and 23 are set forth above.
The combination of Hagel, Kang, Jiang, Trantas, and Koopman does not teach or suggest overproducing S-adenosylmethionine.
Cao teaches S-adenosyl-L-methionine (SAM) is an essential metabolite in all living cells, plays an important role in cellular functions (p. 1395, column 1, Abstract), and exhibits pivotal roles in various biological reactions (p. 1395, column 2, top). Cao teaches subjecting a S. cerevisiae to mutagenesis with UV irradiation to achieve a rapid improvement of SAM production (p. 1395, column 1, Abstract) and teaches various other alternative methods of enhancing SAM production by S. cerevisiae (p. 1399, column 2 and p. 1400, column 2).
In view of the combined teachings of Hagel, Kang, Jiang, Trantas, Koopman, and Cao, it would have been obvious to one of ordinary skill in the art before the effective filing date for the S. cerevisiae expressing PAL, C4H, 4CL, CPR, TYDC, and THT as taught and/or suggested by the combination of Hagel, Kang, Jiang, and Trantas to overproduce SAM. One would have been motivated in order to optimize the S. cerevisiae expressing PAL, C4H, 4CL, CPR, TYDC, and THT as taught and/or suggested by the combination of Hagel, Kang, Jiang, and Trantas because Cao taught SAM is an essential metabolite in all living cells, plays an important role in cellular functions, and exhibits pivotal roles in various biological reactions. One would have expected success because Cao taught multiple methods of enhancing SAM production by S. cerevisiae.
Therefore, claim 3 would have been obvious to one of ordinary skill in the art before the effective filing date.
RESPONSE TO REMARKS: In summary, applicant argues Trantas is directed to an objective that is fundamentally different from the production of tyramine-containing hydroxycinnamic acid amides; one would not have applied the S. cerevisiae expressing the plant phenylpropanoid enzymes PAL, C4H, 4CL, and CPR of Trantas to the production of tyramine-containing hydroxycinnamic acid amides; and none of the other cited references cures this alleged deficiency.
Applicant’s arguments are not found persuasive. Applicant has addressed Trantas as well as each of the other cited references individually rather than considering the combination of cited prior art. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See MPEP 2145.IV.
Contrary to applicant’s position, when the cited prior art is taken in combination, one of ordinary skill in the art would have recognized that the teachings of Trantas are relevant to the production of tyramine-containing hydroxycinnamic acid amides. Trantas taught modifying a S. cerevisiae to express the plant phenylpropanoid pathway enzymes PAL, C4H, 4CL, and CPR for production of 4-coumaroyl-CoA, which is the same intermediate that is combined with tyramine to produce hydroxycinnamic acid amides as taught by Hagel and Kang. Given the advantages of S. cerevisiae as taught by Jiang and the similarities of S. cerevisiae to plants as taught by Trantas, it would have been obvious in view of the combined teachings of Hagel, Kang, Jiang, and Trantas to make a S. cerevisiae expressing PAL, C4H, 4CL, CPR, TYDC, and THT for the production of hydroxycinnamic acid amides.
For the reasons set forth above, it is the examiner’s position that the claimed invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Conclusion
Status of the claims:
Claims 1-3, 6, 7, 22, and 23 are pending in the application.
Claims 1-3, 6, 7, 22, and 23 are rejected.
No claim is in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID J STEADMAN whose telephone number is (571)272-0942. The examiner can normally be reached Monday to Friday, 7:30 AM to 4:00 PM.
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/David Steadman/Primary Examiner, Art Unit 1656
APPENDIX A
Figures 3 (top) and 7 (bottom) of Hagel
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APPENDIX B
Figure 1.2 of Jiang
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APPENDIX C
Figure 2 of Trantas
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Prosecution Insights